It is well known that most eicosanoids, prostaglandins, leukotrienes and related compounds derive from a fatty acid having 20 carbons and 4 unsaturations, called arachidonic acid (AA), which fundamentally esterifies the hydroxyl at the 2-position of the glycerol of the phospholipids contained in the cell membranes. AA is released from the phospholipid containing it by the action of a lipase, phospholipase A.sub.2 (PLA.sub.2) ("CRC Handbook of Eicosanoids and Related Lipids", vol. II, Ed. A. L. Willis, CRS Press Inc., Florida (1989)). After being released AA is metabolized in mammals mainly by two different pathways or enzyme systems. Through cyclooxygenase it produces prostaglandins and thromboxanes, the most significant being PGE.sub.2 and TxA.sub.2, which are directly involved in inflammation (Higgs et al. Annals of Clinical Research, 16, 287 (1984)). Through lipoxygenase it produces leukotrienes, the most important being LTB.sub.4, and the peptide-leukotrienes LTC.sub.4, LTD.sub.4 and LTE.sub.4. All of them are also involved in inflammatory reactions, exhibiting chemotactic activities, stimulating the secretion of lysosomic enzymes and playing an important role in immediate hypersensitivity reactions (Bailey and Casey, Ann. Rep. Med. Chem., 17, 203 (1982)). Leukotriene LTB.sub.4 is a strong chemotactic agent which promotes the infiltration of leukocytes and their subsequent degranulation. (Salmon et al., Prog. Drug Res., 37, 9 (1991)). It has been widely shown that LTC.sub.4 and LTD.sub.4 have strong constrictive action on human bronchi (Dahlen et al., Nature, 288, 484 (1980)), causing the obstruction of airways by inflammation and mucus production (Marom et al., Am. Rev. Resp. Dis., 126, 449 (1982)), being thus involved in the pathogenesis of bronchial asthma, chronic bronchitis, allergic rhinitis, etc. Peptide-leukotrienes also bring about a blood extravasation caused by the increase of vascular permeability (Camp et al., Br. J. Pharmacol., 80, 497 (1883)) and are involved in some inflammatory diseases such as atopic eczema and psoriasis. On the other hand, several effects of peptide-leukotrienes on human cardiovascular system have been observed; they are mainly involved in the pathogenesis of the ischaemic cardiopathy. This relationship has been confirmed by the fact that coronary arteries can produce these mediators (Piomelli et al., J. Clin. Res., 33, 521A (1985)). These effects, together with the strong contractions observed in heart tissue caused by LTC.sub.4 and LTD.sub.4, suggest that these mediators might contribute to other cardiovascular disorders, such as coronary spasm, heart anaphylaxis, cerebral oedema and endotoxic shock.
From what said above it follows that the control of the biological activity of leukotrienes through compounds which inhibit their release or antagonize their effects, represents a new rational approach to the prevention, elimination or improvement of different allergic, anaphylactic, inflammatory and thrombotic conditions, in which such mediators are involved.
In literature some compounds have been described that can be considered as structurally related to the compounds of the present invention, having moreover an inhibitory action on leukotrienes. Toda M. et al. described N-[4-oxo-2-(1H-5-tetrazolyl)-4H-1-benzopyran-8-yl]-4-(4-phenylbutoxy)benza mide and the derivatives thereof (EP 173,516) as strong leukotriene antagonists. All these derivatives have an amide or thioamide group in their structure as a bridge between a lipophilic moiety and a carbocycle containing an acid moiety. Therefore, the compounds disclosed in the present invention, besides other functional groups as bridges between other lipophilic and polar moieties, can have amides as well, in any case such derivatives being not included within the general formula of the patent of Toda et al. On the other hand, the derivatives of the present invention show the advantage of a very high oral bioavailability thanks to their metabolic and/or chemical stability.
On the other hand, Huang F. C. et al. (U.S. Pat. No. 4,977,162 and U.S. Pat. No. 5,082,849) described 4-oxo-7-[[3-(2-quinolinylmethoxy)phenyl]methyloxy]-2-(1H-5-tetrazolyl)-4H- 1-benzopyran and the derivatives thereof as potent leukotriene antagonists. All of said compounds are quinoline derivatives containing ethers, thioethers, sulfoxides, sulfones, amides, ketones, vinylenes and amines as bridges between the chromane heterocycle or equivalent with an acid function and the quinoline-containing lipophilic moiety. Therefore such compounds differ from those of the present invention in that they contain a quinoline within their general formulae, which heterocycle is never present in the general formulae and claims of the present invention.
However, the obtention of compounds with high leukotriene antagonistic activity and good oral bioavailability is still an unresolved problem in a number of antagonists up to now. The present invention provides a series of novel compounds that exhibit the above mentioned antagonistic action, that show a good oral adsorption and are useful in therapy.